To determine the importance of genes located in or near the Ig constant regions in regulating the human antibody response, we correlated Ig allotypic markers with total Ig concentrations and natural antibody concentrations to the streptococcal group A carbohydrate (A-CHO) in 193 healthy adult blood donors. The major correlations between Ig allotypes and total Ig and specific antibody concentrations were observed with the Gm(f;n;b) haplotype. When compared with Gm(f;n;b) negative individuals, Gm(f;n;b) positives had significantly higher concentrations of total IgG2 (p less than 0.001) and IgG2 anti A-CHO (p less than 0.05), lower concentrations of total IgG1 (p less than 0.001) and IgG1 anti A-CHO (p less than 0.001), and lower concentrations of total IgM (p less than 0.001) and IgM anti A-CHO (p less than 0.05). We conclude that individuals with the Gm(f;n;b) haplotype respond preferentially with IgG2 rather than IgG1 subclass antibodies. This increased capacity to respond with IgG2 antibodies may be reflected in the magnitude of the total antibody response when the IgG2 subclass comprises a major proportion of the response, as occurs in the adult response to many polysaccharide Ag.